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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Blockade of adenosine A2A receptors downregulates DARPP-32 but increases ERK1/2 activity in striatum of dopamine deficient 'weaver' mouse.
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Blockade of adenosine A2A receptors downregulates DARPP-32 but increases ERK1/2 activity in striatum of dopamine deficient 'weaver' mouse.

机译：腺苷A2A受体的阻滞下调DARPP-32，但增加多巴胺缺乏的“编织者”小鼠纹状体中的ERK1 / 2活性。

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摘要

In the present study we investigated the signal transduction cascade modulated by adenosine A(2A) receptors under chronic dopamine deficiency in the "weaver" mouse. We determined the phosphorylation state of cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr34 and of Extracellular Signal-regulated Protein Kinases 1/2 (ERK1/2), under basal conditions and after in vivo stimulation of A(2A) receptors by administration of the agonist CGS21680. Our results revealed that the endogenous levels of phospho-DARPPP-32 and phospho-ERK1/2 are elevated in "weaver" striatum probably as an adaptation phenomenon to gradual dopaminergic neurodegeneration appearing in this animal model, characterized as phenocopy of Parkinson's disease. Stimulation of A(2A) receptors by CGS21680 further increases phospho-DARPP-32 but downregulates significantly the elevated phospho-ERK1/2 levels bringing them close to those observed in wild type animals. Consistently, blockade of A(2A) receptors by MSX-3 (A(2A) receptor antagonist) downregulates phospho-DARPP-32 but significantly increases even more the phosphorylation/activation of ERK1/2. These results indicate that under chronic dopamine deficiency (a) the A(2A)/cAMP/PKA/DARPP-32 cascade is overactive due to the elevated endogenous phospho-DARPP-32 levels and (b) the A(2A) receptor modulatory effect on ERK1/2 signaling is dysregulated exerting opposing action compared to that observed in normal animals (Quiroz et al., 2006), i.e. in weaver cascade. This could be of clinical relevance since A(2A) antagonists are already used in clinical trials for ameliorating Parkinson's disease (PD) symptoms.
机译：在本研究中，我们研究了在“织布工”小鼠中在慢性多巴胺缺乏下由腺苷A（2A）受体调节的信号转导级联反应。我们确定了在基础条件下和在体内刺激A（2A）后，在Thr34处cAMP调节的32 kDa磷酸蛋白（DARPP-32）和细胞外信号调节的蛋白激酶1/2（ERK1 / 2）的磷酸化状态。通过给予激动剂CGS21680受体。我们的研究结果表明，在“织布”纹状体中，内源性磷酸-DARPPP-32和磷酸-ERK1 / 2的水平升高，可能是对该动物模型中出现的逐渐多巴胺能神经变性的适应现象，其特征为帕金森氏病的表型。 CGS21680刺激A（2A）受体进一步增加了磷酸-DARPP-32，但显着下调了升高的磷酸-ERK1 / 2水平，使其接近野生型动物中观察到的水平。一致地，MSX-3（A（2A）受体拮抗剂）对A（2A）受体的阻断下调了磷酸-DARPP-32，但显着增加了ERK1 / 2的磷酸化/激活。这些结果表明，在慢性多巴胺缺乏症下，（a）A（2A）/ cAMP / PKA / DARPP-32级联由于内源性磷酸-DARPP-32水平升高而过度活跃，并且（b）A（2A）受体调节作用与正常动物（Quiroz等，2006）中观察到的，即在织布工级联中观察到的相比，ERK1 / 2的信号传导失调，发挥相反的作用。这可能具有临床意义，因为A（2A）拮抗剂已经在临床试验中用于缓解帕金森氏病（PD）症状。

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